15-86224921-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001386094.1(AGBL1):c.496A>G(p.Thr166Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: AGBL1 NM_001386094.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.649

Genes affected

AGBL1 (HGNC:26504): (AGBL carboxypeptidase 1) Polyglutamylation is a reversible posttranslational modification catalyzed by polyglutamylases that results in the addition of glutamate side chains on the modified protein. This gene encodes a glutamate decarboxylase that catalyzes the deglutamylation of polyglutamylated proteins. Mutations in this gene result in dominant late-onset Fuchs corneal dystrophy. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.089256525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGBL1	NM_001386094.1	c.496A>G	p.Thr166Ala	missense_variant	6/23	ENST00000614907.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGBL1	ENST00000614907.3	c.496A>G	p.Thr166Ala	missense_variant	6/23	5	NM_001386094.1	P4
AGBL1	ENST00000441037.7	c.496A>G	p.Thr166Ala	missense_variant	6/25	5		A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461266 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.358A>G (p.T120A) alteration is located in exon 5 (coding exon 4) of the AGBL1 gene. This alteration results from a A to G substitution at nucleotide position 358, causing the threonine (T) at amino acid position 120 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	14
Dann	Benign	0.97
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.56	T;.
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
REVEL	Benign	0.058
Polyphen		0.0010	.;B
MutPred		0.54		.;Loss of phosphorylation at T120 (P = 0.1684);
MVP		0.076
MPC		0.010
ClinPred		0.080	T
GERP RS		-0.046
Varity_R		0.068
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs768610169; hg19: chr15-86768152;